Project 1. Avoidance of autoimmunity relies on carefully regulated and appropriate interplay between genetics, the environment, and components of both the innate and adaptive (acquired) immune systems; a central hypothesis to this P01. Given the innate immune system's role in monitoring the microbiologic and biochemical environments, and providing rapid protective acquired immune responses, it is well positioned to break tolerance in response to environmental signals. Dendritic Cells [DC] provide this linkage, in part, through pattern recognition receptors [e.g., toll like receptors [TLR], and retinoic acid-induced gene 1-likereceptors [RLR] that detect bacterial/viral/biochemical and self molecular signatures leading td DC activation and inflammation. DC activation by TLR/RLR results in Type 1 interferons [IFN?/?] that drive DC maturation, THI, antibody, and CTL responses. Project 1 poses an interdigitating hypothesis; the conjoint defects in type 1 IFN biology, hyperactive IFN?/? responses and increased plasmacytoid DC (PDC)/IFN?/? production in the islet microenvironment play a critical role in T1D pathogenesis. These defects, investigated with Project 2, promote; a) loss of B cell function, b) immunogenic DC, c) pro-inflammatory macrophages [MF], d) THI responses, e) enhanced CTL and p cell killing and f) downgrading of protective Treg and iNKT cell responses. As a corollary, the defects reach full potential when PDC or other immune cells are activated by exogenous or endogenous factors that stimulate IFN?/? production, linking environment and immunogenetics. In addition, a major emphasis will be to evaluate the effect of specific candidate genotypes, (Ifihl,Tyk2) identified in genome wide association studies (GWAS) and affecting IFN?/? biology, on specific immune cell function and p cell function. We believe Project 1 finds marked significance and innovation through the integrative approach afforded by the P01 mechanism (with Project 2), and quite importantly, our ability to explore lymphoid and pancreatic tissues from the nPOD program.